全文获取类型
收费全文 | 1819篇 |
免费 | 117篇 |
出版年
2023年 | 11篇 |
2022年 | 23篇 |
2021年 | 46篇 |
2020年 | 20篇 |
2019年 | 35篇 |
2018年 | 44篇 |
2017年 | 33篇 |
2016年 | 47篇 |
2015年 | 79篇 |
2014年 | 95篇 |
2013年 | 106篇 |
2012年 | 118篇 |
2011年 | 124篇 |
2010年 | 72篇 |
2009年 | 79篇 |
2008年 | 98篇 |
2007年 | 91篇 |
2006年 | 81篇 |
2005年 | 64篇 |
2004年 | 72篇 |
2003年 | 63篇 |
2002年 | 57篇 |
2001年 | 24篇 |
2000年 | 26篇 |
1999年 | 26篇 |
1998年 | 14篇 |
1997年 | 15篇 |
1996年 | 12篇 |
1995年 | 11篇 |
1993年 | 8篇 |
1992年 | 14篇 |
1991年 | 16篇 |
1990年 | 19篇 |
1989年 | 18篇 |
1988年 | 21篇 |
1987年 | 25篇 |
1986年 | 26篇 |
1985年 | 18篇 |
1984年 | 16篇 |
1983年 | 17篇 |
1982年 | 13篇 |
1981年 | 11篇 |
1980年 | 8篇 |
1979年 | 12篇 |
1978年 | 21篇 |
1977年 | 7篇 |
1976年 | 13篇 |
1975年 | 9篇 |
1971年 | 5篇 |
1968年 | 5篇 |
排序方式: 共有1936条查询结果,搜索用时 328 毫秒
161.
Rackham O Shearwood AM Thyer R McNamara E Davies SM Callus BA Miranda-Vizuete A Berners-Price SJ Cheng Q Arnér ES Filipovska A 《Free radical biology & medicine》2011,50(6):689-699
The cytosolic and mitochondrial thioredoxin reductases (TrxR1 and TrxR2) and thioredoxins (Trx1 and Trx2) are key components of the mammalian thioredoxin system, which is important for antioxidant defense and redox regulation of cell function. TrxR1 and TrxR2 are selenoproteins generally considered to have comparable properties, but to be functionally separated by their different compartments. To compare their properties we expressed recombinant human TrxR1 and TrxR2 and determined their substrate specificities and inhibition by metal compounds. TrxR2 preferred its endogenous substrate Trx2 over Trx1, whereas TrxR1 efficiently reduced both Trx1 and Trx2. TrxR2 displayed strikingly lower activity with dithionitrobenzoic acid (DTNB), lipoamide, and the quinone substrate juglone compared to TrxR1, and TrxR2 could not reduce lipoic acid. However, Sec-deficient two-amino-acid-truncated TrxR2 was almost as efficient as full-length TrxR2 in the reduction of DTNB. We found that the gold(I) compound auranofin efficiently inhibited both full-length TrxR1 and TrxR2 and truncated TrxR2. In contrast, some newly synthesized gold(I) compounds and cisplatin inhibited only full-length TrxR1 or TrxR2 and not truncated TrxR2. Surprisingly, one gold(I) compound, [Au(d2pype)(2)]Cl, was a better inhibitor of TrxR1, whereas another, [(iPr(2)Im)(2)Au]Cl, mainly inhibited TrxR2. These compounds also inhibited TrxR activity in the cytoplasm and mitochondria of cells, but their cytotoxicity was not always dependent on the proapoptotic proteins Bax and Bak. In conclusion, this study reveals significant differences between human TrxR1 and TrxR2 in substrate specificity and metal compound inhibition in vitro and in cells, which may be exploited for development of specific TrxR1- or TrxR2-targeting drugs. 相似文献
162.
Prast-Nielsen S Dexheimer TS Schultz L Stafford WC Cheng Q Xu J Jadhav A Arnér ES Simeonov A 《Free radical biology & medicine》2011,50(9):1114-1123
The selenoprotein thioredoxin reductase 1 (TrxR1) has in recent years been identified as a promising anticancer drug target. A high-throughput assay for discovery of novel compounds targeting the enzyme is therefore warranted. Herein, we describe a single-enzyme, dual-purpose assay for simultaneous identification of inhibitors and substrates of TrxR1. Using this assay to screen the LOPAC1280 compound collection we identified several known inhibitors of TrxR1, thus validating the assay, as well as several compounds hitherto unknown to target the enzyme. These included rottlerin (previously reported as a PKCδ inhibitor and mitochondrial uncoupler) and the heme precursor protoporphyrin IX (PpIX). We found that PpIX was a potent competitive inhibitor of TrxR1, with a Ki = 2.7 μM with regard to Trx1, and in the absence of Trx1 displayed time-dependent irreversible inhibition with an apparent second-order rate constant (kinact) of (0.73 ± 0.07) × 10? 3 μM? 1 min? 1. Exogenously delivered PpIX was cytotoxic, inhibited A549 cell proliferation, and was found to also inhibit cellular TrxR activity. Hemin and the ferrochelatase inhibitor NMPP also inhibited TrxR1 and showed cytotoxicity, but less potently compared to PpIX. We conclude that rottlerin-induced cellular effects may involve targeting of TrxR1. The unexpected finding of PpIX as a TrxR1 inhibitor suggests that such inhibition may contribute to symptoms associated with conditions of abnormally high PpIX levels, such as reduced ferrochelatase activity seen in erythropoietic protoporphyria. Finally, additional inhibitors of TrxR1 may be discovered and further characterized based upon the new high-throughput TrxR1 assay presented here. 相似文献
163.
The continual destruction and renewal of proteins that maintain cellular homeostasis has been rigorously studied since the late 1930s. Experimental techniques for measuring protein turnover have evolved to measure the dynamic regulation of key proteins and now, entire proteomes. In the past decade, the proteomics field has aimed to discover how cells adjust their proteomes to execute numerous regulatory programs in response to specific cellular and environmental cues. By combining classical biochemical techniques with modern, high-throughput technologies, researchers have begun to reveal the synthesis and degradation mechanisms that shape protein turnover on a global scale. This review examines several recent developments in protein turnover research, emphasizing the combination of metabolic labeling and mass spectrometry. 相似文献
164.
Cheng Z Elias DR Kamat NP Johnston ED Poloukhtine A Popik V Hammer DA Tsourkas A 《Bioconjugate chemistry》2011,22(10):2021-2029
Block copolymer-based vesicles have recently garnered a great deal of interest as nanoplatforms for drug delivery and molecular imaging applications due to their unique structural properties. These nanovesicles have been shown to direct their cargo to disease sites either through enhanced permeability and retention or even more efficiently via active targeting. Here, we show that the efficacy of nanovesicle targeting can be significantly improved when prepared from polymer-lipid blends compared with block copolymer alone. Polymer-lipid hybrid nanovesicles were produced from the aqueous coassembly of the diblock copolymer, poly(ethylene oxide)-block-polybutadiene (PEO-PBD), and the phospholipid, hydrogenated soy phosphatidylcholine (HSPC). The PEG-based vesicles, 117 nm in diameter, were functionalized with either folic acid or anti-HER2/neu affibodies as targeting ligands to confer specificity for cancer cells. Our results revealed that nanovesicles prepared from polymer-lipid blends led to significant improvement in cell binding compared to nanovesicles prepared from block copolymer alone in both in vitro cell studies and murine tumor models. Therefore, it is envisioned that nanovesicles composed of polymer-lipid blends may constitute a preferred embodiment for targeted drug delivery and molecular imaging applications. 相似文献
165.
de Lira FA Farias Mde S de Figueiredo AF Gil Fdos S dos Santos MA Malheiros BV Ferreira JE Pinheiro JC Treu-Filho O Kondo RT 《Journal of molecular modeling》2011,17(7):1621-1624
In a previous article, we used Hartree-Fock (HF) theory to study the piezoelectricity in BaTiO3. In this paper, we applied the Douglas-Kroll-Hess second order scalar relativistic method to investigate the possible piezoelectric
properties in the perovskite YFeO3 structure, which has not yet been studied experimentally. The 30s20p13d and 31s21p17d Gaussian basis sets for the Fe (5D) and Y (2D) atoms, respectively, were built with the Generator Coordinate HF method. After contraction to [13s7p5d] and [13s8p7d],
in combination with the 20s14p/6s4p basis set for the O (3P) atom from literature, they had their quality evaluated using calculations of the total and the orbital energies for the
2FeO+1 and 1YO+1 fragments. The dipole moment, the total energy, and the total atomic charges in YFeO3 in Cs space group were calculated. The results and the analysis lead us to believe that the perovskite YFeO3 does not present piezoelectric properties. 相似文献
166.
Robert P. Smith Bruce Cahill Charles Lubelczyk Susan P. Elias Eleanor Lacombe Sara R. Morris Calvin P. Vary Christine E. Parent Peter W. Rand 《Journal of vector ecology》2011,36(1):24-29
The role of migratory birds in the dispersal of Ixodes scapularis ticks in the northeastern U.S. is well established and is presumed to be a major factor in the expansion of the geographic risk for Lyme disease. Population genetic studies of B. burgdorferi sensu stricto, the agent of Lyme disease in this region, consistently reveal the local presence of as many as 15 distinct strain types as designated by major groups of the ospC surface lipoprotein. Recent evidence suggests such strain diversity is adaptive to the diverse vertebrate hosts that maintain enzootic infection. How this strain diversity is established in emergent areas is unknown. To determine whether similar strain diversity is present in ticks imported by birds, we examined B. burgdorferi strains in I. scapularis ticks removed from migrants at an isolated island site. Tick mid‐guts were cultured and isolates underwent DNA amplification with primers targeting ospC. Amplicons were separated by gel electrophoresis and sequenced. One hundred thirty‐seven nymphal ticks obtained from 68 birds resulted in 24 isolates of B. burgdorferi representing eight ospC major groups. Bird‐derived ticks contain diverse strain types of B. burgdorferi, including strain types associated with invasive Lyme disease. Birds and the ticks that feed on them may introduce a diversity of strains of the agent of Lyme disease to emergent areas. 相似文献
167.
Estrada-Barraza D Dávalos Martínez A Flores-Padilla L Mendoza-De Elias R Sánchez-Vargas LO 《Revista iberoamericana de micología》2011,28(1):36-42
The increase in the incidence of yeast species causing fungemia in susceptible immunocompromised patients in the last two decades and the low sensitivity of conventional blood culture has led to the need to develop alternative approaches for the early detection and identification of causative species. The aim of this study was to compare the usefulness of molecular testing by the polymerase chain reaction (PCR) and conventional methods to identify clinical isolates of different species, using the ID32C ATB system (bioMérieux, France), chromogenic culture Chromagar Candida? (CHROMagar, France) and morphogenesis in corn meal agar. We studied 79 isolates, in which the most prevalent species using the system ID32C and PCR was C. albicans, followed by C. tropicalis, C. glabrata and C .krusei. PCR patterns obtained for the identification of clinical isolates were stable and consistent in the various independent studies and showed good reproducibility, concluding that PCR with species-specific primers that amplify genes ITS1 and ITS2 for rRNA or topoisomerase II primers is a very specific and sensitive method for the identification of C. glabrata, C. krusei, C. albicans, and with less specificity for C. tropicalis. 相似文献
168.
169.
Background
Body change illusions have been of great interest in recent years for the understanding of how the brain represents the body. Appropriate multisensory stimulation can induce an illusion of ownership over a rubber or virtual arm, simple types of out-of-the-body experiences, and even ownership with respect to an alternate whole body. Here we use immersive virtual reality to investigate whether the illusion of a dramatic increase in belly size can be induced in males through (a) first person perspective position (b) synchronous visual-motor correlation between real and virtual arm movements, and (c) self-induced synchronous visual-tactile stimulation in the stomach area.Methodology
Twenty two participants entered into a virtual reality (VR) delivered through a stereo head-tracked wide field-of-view head-mounted display. They saw from a first person perspective a virtual body substituting their own that had an inflated belly. For four minutes they repeatedly prodded their real belly with a rod that had a virtual counterpart that they saw in the VR. There was a synchronous condition where their prodding movements were synchronous with what they felt and saw and an asynchronous condition where this was not the case. The experiment was repeated twice for each participant in counter-balanced order. Responses were measured by questionnaire, and also a comparison of before and after self-estimates of belly size produced by direct visual manipulation of the virtual body seen from the first person perspective.Conclusions
The results show that first person perspective of a virtual body that substitutes for the own body in virtual reality, together with synchronous multisensory stimulation can temporarily produce changes in body representation towards the larger belly size. This was demonstrated by (a) questionnaire results, (b) the difference between the self-estimated belly size, judged from a first person perspective, after and before the experimental manipulation, and (c) significant positive correlations between these two measures. We discuss this result in the general context of body ownership illusions, and suggest applications including treatment for body size distortion illnesses. 相似文献170.
Burridge PW Thompson S Millrod MA Weinberg S Yuan X Peters A Mahairaki V Koliatsos VE Tung L Zambidis ET 《PloS one》2011,6(4):e18293